We report herein the synthesis of a series of 7-[3-alkoxyimino-4-(methyl)aminopiperidin-1-yl]quinolone/naphthyridone derivatives. In vitro antibacterial activity of these derivatives was evaluated against representative strains, and compared with ciprofloxacin (CPFX), levofloxacin (LVFX) and gemifloxacin (GMFX). The results reveal that all of the target compounds 19a-c and 20 have considerable Gram-positive activity, although they are generally less active than the reference drugs against the Gram-negative strains with some exceptions. Especially, novel compounds 19a2, 19a4 and 19a5 were found to show strong antibacterial activity (MICs: <0.008-0.5μg/mL) against all of the tested 15 Gram-positive strains including MRSA, LVFX- and GMFX-resistant MRSE, and CPFX-, LVFX- and GMFX-resistant MSSA.